This is the National Phase Application of PCT EP00/08646 filed Sep. 5, 2000.
The present invention relates to a composition for producing a satiation effect.
Numerous attempts have been made by medical means to break down excessive accumulations of fat in the human body, or to prevent them developing. There are, for example, appetite suppressants which attempt by biochemical means to induce in the body a disinclination to take food. These compositions have in some cases considerable harmful side effects.
Besides the numerous dietary products which have been proposed, there are also mechanical and electromechanical means intended specifically to break down fat and build up muscle. However, the effect of such means is very doubtful.
German Patent DE 402,5912 discloses a composition for oral intake which consists of a container which is soluble in the stomach and releases the contents. This container is filled with a substance whose volume increases after it is released in the stomach, and thus it induces a feeling of satiation in the body.
From the prior art a number of elastic materials are already known that can be compressed on passage through the esophagus and which can, after leaving the esophagus, be decompressed in water and/or gastrointestinal fluid. Such sponge-like structures are taken to mean foams which consist of gas-filled spherical/polyhedral cells which are limited by highly viscous or solid cell walls. It is possible to employ according to the invention both naturally occurring sponges and synthetically prepared sponge-like structures.
Natural materials which are already used are collagen and cellulose. However, these abovementioned materials are relatively expensive raw materials. Both materials require complex isolation or work-up processes which, in addition, are very environmentally polluting. The latter applies especially to cellulose, the isolation of which means that large amounts of acids have to be employed.
Soluble collagen is isolated from animal hides, for example, preferably young cattle or pigs, since the soluble collagen content in the animal becomes ever smaller with increasing age. This is also only possible with complex isolation and work-up processes.
Not least since the discovery of a number of diseases in pigs and cattle, which are suspected to be transmissible to humans, in particular the cattle disease BSE, and a possible risk of infection for humans, the acceptance of such collagen-containing products by the end consumer has fallen drastically.
It is an object of the present invention, therefore, to provide a material for preparing a composition for producing a long-lasting satiation effect, which material does not have the abovementioned disadvantages.
This is achieved according to the invention by a composition for oral intake comprising uronic-acid-containing polysaccharides stably crosslinked to one another in the form of a sponge-like structure which is characterized in that it is slightly soluble or of low absorbability in water and/or gastrointestinal fluids.
According to the invention the uronic-acid-containing polysaccharides are crosslinked to one another by ionic bonds and in addition are stably crosslinked to one another by covalent bonds. Particularly preferred polyuronic acid-containing-polysaccharides are alginic acids and their salts (alginates). However, low degree of esterification pectins, xanthan, tragacanth, chondroitin sulfate and all other uronic-acid-containing compounds can also be used according to the invention.
Alginic acid is a linear polyuronic acid of alternating parts of D-mannuronic acid and L-guluronic acid which are linked to one another by xcex2-glycosidic bonds, the carboxyl groups not being esterified. One molecule of alginic acid can be composed of about 150-1 050 uronic acid units, where the mean molecular weight can range from 30-200 kDa.
The polysaccharide alginic acid is a constituent of cell walls of brown algae. The alginic acid content can make up to 40% of the dry matter of the algae in this case. The alginic acid is produced by alkaline extraction with methods known per se according to the prior art. The resultant pulverulent alginic acid is thus purely of plant origin and has high biocompatibility. It can absorb 300 times its own weight of water, forming highly viscous solutions. In the presence of polyvalent cations, alginic acid forms gels. The formation of alginate gels in the presence of divalent cations, such as calcium or barium, is described in Shapiro I., et al. (Biomaterials, 1997, 18: 583-90). The latter is not suitable for use in biomedicine, however, on account of its toxicity. In addition to calcium chloride, calcium gluconate also provides suitable divalent cations. In general, all physiologically safe polycations can be used, in particular divalent cations. The unbranched concertina-like alginate chains are fixed by ionic bonds via the free bonding positions of the cations, preferably calcium ions (FIG. 1). This produces a three-dimensional network in which the divalent cations are situated like xe2x80x9ceggs in an eggboxxe2x80x9d as in the xe2x80x9cegg-box modelxe2x80x9d presented in Smidsrod et al. (Trends in Biotechnology, 1990, 8: 71).
The sponge-like or sponge-shaped structures are produced by methods known per se from the prior art. Depending on the starting material employed, in the simplest case, a foam can be obtained by blowing, by beating, shaking, spraying or stirring in the relevant gas atmosphere. In the case of polymers, the foam structure is produced by chemical reactions. Thus, for example, polyurethanes are foamed by adding blowing agents which decompose at a defined temperature during processing, with gas formation, or by addition of liquid solvents during the polymerization. The foaming takes place either on leaving the extrusion die, that is to say following the extrusion or injection molding, or in open molds. The curing takes place under the conditions characteristic of the respective chemical compound of the material.
An indispensable prerequisite for the usability of the material is that it can be compressed without breaking the cell walls. This is because in order to be able to use the inventive material for oral intake, the foam-like or foamy material must be directly compressible on passage through the esophagus. In particular, no trouble must occur on passage through the esophagus.
A particular advantage of the present invention is that the alginates crosslinked according to the invention are more flexible and softer, and as a result have very much more favorable mechanical properties for gastrointestinal application than the materials previously available on the market. For the user this is accompanied by the advantage of improved tolerance, so that even in the case of patients having mucosal lesions, neither a feeling of pressure nor mucosal irritation is caused.
For the selection of the material and the type of foam formation, it is furthermore essential that the material remains swellable without destroying the cell walls. After passage through the esophagus, the sponge-like structure is to resume at least the size which it had before entry into the esophagus. If appropriate, the material may also swell to a size which goes beyond the original volume.
The sponge-like structure can have any desired shape and size in the compressed and decompressed states. However, preference is given to cuboid or rectangular or round embodiments.
Preferably, the material is designed so that the sponge-like structure can be compressed to xc2xd to {fraction (1/100)}, preferably xc2xc to {fraction (1/50)}, particularly preferably {fraction (1/10)} to {fraction (1/20)}, of its volume or of its size. Under physiological conditions, the compressed material, after passage through the esophagus, is to be able to expand, preferably to two to twenty times, particularly preferably to four to fifty times, and very particularly preferably to ten to twenty times, its volume.
As material for the sponge-like structure, according to the invention natural, semisynthetic or synthetic polymers can be used, which, in addition, can be crosslinked by stable crosslinks.
Various processes are known from the prior art for crosslinking polymers. Thus, for example, the free-radical polymerization of lactose-O-(p-vinylbenzyl)oxime for forming hydrogels is described in Zhou, W-Z, et al. (Macromolecules, 1997, 30: 7063-7068) and a polymerization of N-vinylpyrrolidone by electron-beam irradiation is described in Rosiak, J. M. (J Contr Rel., 1994, 31: 9-19). In addition, for example, crosslinked polymers of saccharide acrylates or poly(2-hydroxyethylmethacrylate)gelatin and also collagen or chitosan are known (Martin, B. D., et al. (Biomaterials, 1998, 19: 69-76; Santin, M., et al. (Biomaterials, 1996, 17: 1459-1467); Weadock, K. S., et al. (J Biomed Mater Res, 1995, 29: 1371-1379); Groboillot, A., et al. (Biotech Bioeng, 1993, 42: 1157-1163)).
Examples of starting materials particularly suitable according to the invention are uronic-acid-containing polysaccharides which still have free reactive groups, preferably carboxyl groups and/or hydroxyl groups, for forming stable crosslinks, for example ester bonds. Very high preference is given here to alginic acids, low degree of esterification pectins, xanthan, tragacanth, chondroitin sulfate and all uronic-acid-containing compounds and their salts.
Crosslinking alginates by polyvalent cations is described in Shapiro L. et al., Biomaterials, 1997, 18:583-590. However, these compounds are unstable in water or a surrounding medium having a calcium concentration less than 3 mmolar, since the calcium is extracted from the chain cluster and/or may be displaced by other (monovalent) ions. This leads to a dissolution of the crosslinking between the concertina-like polyuronic-acid-containing polysaccharide chains. It is a disadvantage here that the alginates which are only crosslinked by ionic bonds dissolve relatively rapidly in water and/or gastrointestinal fluids and are thus not suitable for producing a satiation effect. A particular advantage of the inventive composition is stable crosslinking by covalent bonds, in particular ester bonds, the formation of which is catalyzed by mineral acids. Covalently linked alginate molecules have also already been described in Moe et al. (Food Hydrocolloids, 1991, 119). However, the preparation process requires relatively long reaction times. In addition, resultant products, owing to the chemicals used for their production, are toxic and are thus not suitable for the fields of application according to the invention.
The inventive composition can comprise, inter alia, pharmaceutically active substances, foodstuffs or food supplements, for example vitamins, dietary fiber, proteins, minerals and other food constituents, taste and stimulant substances or flavorings.
In addition to said substances, it is also possible to add other ancillary substances to the carrier material. Inter alia, release-slowing substances may additionally be suitable in the case where pharmaceutically active substances are used.
In addition, the compositions according to the present invention can additionally contain fillers, disintegrants, binders and lubricants and also excipients.
Active compounds can also be introduced into the sponge-like structure.